In a post-hoc analysis of data from the NICE-SUGAR trial, both moderate and severe hypoglycemia were tied to a significantly higher risk of death even after adjustment for several confounders (P<0.001 for both), Simon Finfer, MD, of the George Institute for International Health in Sydney, and colleagues reported online in the New England Journal of Medicine.

In 2009, the NICE-SUGAR trial found that the risk of death was higher for ICU patients who'd had intensive glucose control compared with standard management.

To look more closely at specific associations between death and moderate and severe hypoglycemia, the researchers conducted a post-hoc analysis of data from the 6,026 patients in the trial who'd had either intensive or conventional blood sugar control.

Overall, 45% had moderate hypoglycemia (defined as blood glucose 41 to 70 mg/dL) and 3.7% had severe hypoglycemia (blood glucose less than 41 mg/dL). The majority of these patients were in the intensive control arm (82.4% and 93.3%, respectively).

A total of 23.5% of patients who didn't have hypoglycemia died during the course of the study, compared with 28.5% of those who had moderate hypoglycemia and 35.4% of those who'd had severe hypoglycemia.

That translated to a significantly increased mortality risk with hypoglycemia, even after adjustment for baseline characteristics and postrandomization factors:

HR 1.41, 95% CI 1.21 to 1.62, P<0.001 for moderate hypoglycemia

HR 2.10, 95% CI 1.59 to 2.77, P<0.001 for severe hypogylcemia

The relationship was stronger for patients who'd been admitted to the ICU immediately out of the operating room compared with non-postop patients (P=0.03) and for those who'd had moderate hypoglycemia on more than one day (P=0.01).

Hypoglycemic patients also had a significantly increased risk of death from distributive, or vasodilated, shock (P<0.001) and from other than cardiovascular, neurologic, or respiratory causes (P=0.002).

The mortality risk was also higher for patients not being treated with insulin, the researchers noted, which suggests that hypoglycemia "may be a marker of impending death rather than a cause of subsequent death."

Indeed, they noted that their study couldn't prove causality, although a "causal relationship is plausible because hypoglycemia may increase mortality by means of impairment of autonomic function, alteration of blood flow and composition, white-cell activation, vasoconstriction, and the release of inflammatory mediators and cytokines."

The study was also limited by intermittent sampling of blood glucose, which means some hypoglycemia may have gone undetected.

Still, Finfer and colleagues concluded, it would "seem prudent to ensure that strategies for managing the blood glucose concentration focus not only on the control of hyperglycemia but also on avoidance of both moderate and severe hypoglycemia," noting that the American Diabetes Association recommends a target blood sugar level of 144 to 180 mg/dL to reduce the risk of hypoglycemia in critically ill patients.

In an accompanying editorial, Irl Hirsch, MD, of the University of Washington, wrote that continuous glucose monitoring in the ICU may be needed to get a better handle on the association between hypoglycemia and death.

Until then, Hirsch said, the best glycemic targets for ICU patients would be those in the NICE-SUGAR study -- 140 to 180 mg/dL -- which match those of the ADA recommendations.

"The use of more conservative glucose targets is unacceptable, and older, nonchalant attitudes need to be abandoned," he wrote, noting, however, that for surgical patients, especially those who've had cardiac procedures, "hospitals that can safely achieve lower targets should do so," given some evidence it may be beneficial in these populations.

The study was supported by the Australian National Health and Medical Research Council, the Health Research Council of New Zealand, and the Canadian Institutes of Health Research.

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